Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

https://doi.org/10.1016/j.semarthrit.2016.05.004Get rights and content

Abstract

Objectives

Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited.

Methods

We have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 (n = 501).

Results

After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were found to have been exposed to tocilizumab shortly before or during pregnancy, with pregnancy outcomes being reported in 288 pregnancies (72.2%). Of these 288 pregnancies, 180 were prospectively reported resulting in 109 live births (60.6%), 39 spontaneous abortions (21.7%), 31 elective terminations of pregnancy (17.2%), and 1 stillbirth. The rate of malformations was 4.5%. Co-medications included methotrexate in 21.1% of the prospectively ascertained cases. Compared to the general population, an increased rate of preterm birth (31.2%) was observed.

Retrospectively reported pregnancies (n = 108) resulted in 55 live births (50.9%), 31 spontaneous abortions (28.7%), and 22 elective terminations (20.4%). Three infants/fetuses with congenital anomalies were reported in this group.

No increased risks for adverse pregnancy outcomes were observed after paternal exposure in 13 pregnancies with known outcome.

Conclusions

No indication for a substantially increased malformation risk was observed. Considering the limitations of global safety databases, the data do not yet prove safety, but provide information for physicians and patients to make informed decisions. This is particularly important after inadvertent exposure to tocilizumab, shortly before or during early pregnancy.

Introduction

Tocilizumab (TCZ) is a recombinant humanized anti-interleukin-6-receptor monoclonal IgG antibody that inhibits the IL-6-mediated signaling pathway [1]. Clinical trials of TCZ demonstrate the therapeutic effectiveness of IL-6 receptor signaling inhibition in patients with rheumatoid arthritis (RA) with inadequate response to disease-modifying antirheumatic drugs (DMARDs), or tumor necrosis factor (TNF) α antagonists [2]. Currently, TCZ has received approval in more than 75 countries worldwide for RA and more recently also for systemic juvenile idiopathic arthritis in children [3]. Efficacy and safety of TCZ as monotherapy or in combination with DMARDs in RA patients insufficiently responsive to DMARDs, or TNF-α-antagonist therapy have been shown [4], [5].

Preclinical data from experimental animal studies suggest that blockade of IL-6-receptor signaling induces no apparent biological effects on fertility or prenatal/postnatal development [6]. TCZ administered to cynomolgus monkeys during early gestation was observed to have no direct or indirect harmful effect on pregnancy or embryo–fetal development. However, a slight increase in abortion/fetal death was observed with high systemic exposure (>100× human exposure) in the 50 mg/kg/day high-dose group compared to placebo and lower doses [7]. Human experience with TCZ exposure in pregnancy is limited to abstracts from conferences [8].

Use of TCZ is not recommended during pregnancy because information regarding the safety of TCZ during pregnancy is extremely limited. However, as many pregnancies are unplanned and RA often concerns women of childbearing potential, there is a need for data to counsel pregnant women inadvertently exposed to TCZ. The evaluation of pregnancy cases from the Roche Global Safety Database is expected to provide basic information in managing pregnancies with TCZ treatment.

Section snippets

Materials and methods

The Roche Global Safety Database records information on pregnancy cases received from clinical trials, spontaneous reports, non-interventional programs or non-interventional studies, and published literature for all Roche products. The pregnancy and neonatal topics MedDRA Standard Query (SMQ) v17.1 was used to retrieve TCZ pregnancy cases from the Roche Global Safety Database, cumulatively up to December 31, 2014.

Pregnancy reports were evaluated independently by two authors (E. Beck and M.

Results

A total of 501 pregnancy-related reports were retrieved from the Roche Global Safety Database until December 31, 2014 (Fig. 1). Most reports concerned maternal exposure and only 22 were related to exposure of the future father. After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were exposed to TCZ before or during pregnancy; pregnancy outcome was reported in 288 (72.2%) of these pregnancies. Prospectively and retrospectively reported patients

Discussion

Our pregnancy outcome study includes the largest dataset of patients with preconception or first trimester exposure to TCZ.

Neither among our 180 prospectively reported pregnancies nor among the 108 retrospective cases a substantially increased rate of congenital malformations was reported, nor was there a distinct pattern of malformations. In most patients of the preconception group (46/54 = 85%) exposure with TCZ occurred during the 6 weeks before conception. Assuming a half-life of 8–14 days

Disclosure statement

Maria Hoeltzenbein, Evelin Beck, Carina Skorpen, and Christof Schaefer declare no conflict of interest. Richa Rajwanshi and Erhan Berber are employees of Genentech/Roche. Monika Ostensen has received speakers fees (<10.000$) from Abbott/Abbvie, Mepha, New Bridge, Pfizer, Roche, and UCB.

Monika Ostensen, Maria Hoeltzenbein, Evelin Beck, Carina Skorpen, Christof Schaefer, Erhan Berber, and Richa Rajwanshi designed the study and revised the manuscript, Erhan Berber and Richa Rajwanshi provided the

Acknowledgements

This work was performed with financial support from the German Ministry of Health (BMG) and the German Federal Institute for Drugs and Medical Devices (BfArM).

Reference List (31)

  • J. Villar et al.

    International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project

    Lancet

    (2014)
  • M. Ostensen et al.

    Autoimmune connective tissue diseases

    Best Pract Res Clin Obstet Gynaecol

    (2015)
  • R. Castilla-Puentes et al.

    Topiramate monotherapy use in women with and without epilepsy: pregnancy and neonatal outcomes

    Epilepsy Res

    (2014)
  • N. Nishimoto et al.

    Humanized antihuman IL-6 receptor antibody, tocilizumab

    Handb Exp Pharmacol

    (2008)
  • M.C. Genovese et al.

    Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study

    Arthritis Rheum

    (2008)
  • G.W. Kim et al.

    IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

    Arch Pharm Res

    (2015)
  • K. Yamamoto et al.

    Longterm safety of tocilizumab: results from 3 years of followup postmarketing surveillance of 5573 patients with rheumatoid arthritis in Japan

    J Rheumatol

    (2015)
  • G. Jones et al.

    Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study

    Ann Rheum Dis

    (2010)
  • T. Sakurai et al.

    The effects of interleukin-6 signal blockade on fertility, embryo-fetal development, and immunization in vivo

    Birth Defects Res B Dev Reprod Toxicol

    (2012)
  • Food and Drug Administration (FDA). Actemra drug approval package. Pharmacology review....
  • K.L. Hyrich et al.

    Biologic therapies and pregnancy: the story so far

    Rheumatology (Oxford)

    (2014)
  • S.D. Reed et al.

    Pregnancy outcomes in women with rheumatoid arthritis in Washington State

    Matern Child Health J

    (2006)
  • World Health Organisation (WHO). Congenital anomalies. 〈http://www.who.int/mediacentre/factsheets/fs370/en/〉 [accessed...
  • European surveillance of congenital anomalies (EUROCAT). Prevalence tables....
  • A. Queisser-Luft et al.

    Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998)

    Arch Gynecol Obstet

    (2002)
  • Cited by (114)

    • Management of Coronavirus Disease-2019 Infection in Pregnancy

      2023, Emergency Medicine Clinics of North America
    • Viral pulmonary infection in pregnancy – Including COVID-19, SARS, influenza A, and varicella

      2022, Best Practice and Research: Clinical Obstetrics and Gynaecology
    View all citing articles on Scopus
    1

    Shared first authorship.

    View full text